Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling.

The differential expression of the critical cell cycle control proteins cyclin D1 and c-myc has been shown to result in Akt-dependent hypersensitivity of tumor cells to mTOR inhibitors. We have previously demonstrated that the differential utilization of internal ribosome entry sites within the mRNAs of these transcripts allows maintenance of protein synthesis in the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA stability is also coordinately regulated following rapa treatment depending on Akt activity status. We identify A/U-rich response elements within the 3' untranslated regions (UTRs) of these transcripts, which confer the observed differential stabilities and show that the RNA-binding protein, tristetraprolin (TTP), interacts with these elements. We also present evidence that TTP accumulates in response to rapa exposure, binds to the cis-acting elements within the cyclin D1 and c-myc 3' UTRs and is differentially serine phosphorylated in an Akt-dependent manner. Furthermore, the differential phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume that the differential control of cyclin D1 and c-myc mRNA stability and translational efficiency constitutes a coordinate response to rapa contributing to the maintenance of expression of these determinants in rapa-resistant quiescent Akt-containing cells following exposure.

Visual responses of neurones in the second visual area of flying foxes (Pteropus poliocephalus) after lesions of striate cortex.

1. The first (V1) and second (V2) cortical visual areas exist in all mammals. However, the functional relationship between these areas varies between species. While in monkeys the responses of V2 cells depend on inputs from V1, in all non-primates studied so far V2 cells largely retain responsiveness to photic stimuli after destruction of V1. 2. We studied the visual responsiveness of neurones in V2 of flying foxes after total or partial lesions of the primary visual cortex (V1). The main finding was that visual responses can be evoked in the region of V2 corresponding, in visuotopic co-ordinates, to the lesioned portion of V1 ('lesion projection zone'; LPZ). 3. The visuotopic organization of V2 was not altered by V1 lesions. 4. The proportion of neurones with strong visual responses was significantly lower within the LPZs (31.5 %) than outside these zones, or in non-lesioned control hemispheres ( > 70 %). LPZ cells showed weak direction and orientation bias, and responded consistently only at low spatial and temporal frequencies. 5. The data demonstrate that the functional relationship between V1 and V2 of flying foxes resembles that observed in non-primate mammals. This observation contrasts with the 'primate-like' characteristics of the flying fox visual system reported by previous studies.